CA2987547A1 - Composition for treating tissue lesions - Google Patents

Abstract

The present invention relates to a pharmaceutical composition including a biocompatible polymer in association with a eukaryotic cell, a platelet extract and/or lysate, or a growth factor, to be used as a drug for the prevention and/or treatment of tissue lesions. The present invention also relates to a pharmaceutical kit which includes a biocompatible polymer in association with a eukaryotic cell for the prevention and/or treatment of tissue lesions. The present invention also relates to the use of a pharmaceutical composition including a biocompatible polymer in association with a eukaryotic cell, a platelet extract and/or lysate, or a growth factor, for manufacturing a drug for the treatment of tissue lesions. The present invention can be used in particular in the veterinary and pharmaceutical fields.

Description

COMPOSITION FOR THE TREATMENT OF TISSUE LESIONS
Technical area The present invention relates to a pharmaceutical composition for its application as a medicine for prevention and / or treatment of tissue lesions.
The present invention also relates to a pharmaceutical kit for the prevention and / or treatment of tissue lesions.
The present invention also relates to the use of a pharmaceutical composition for the manufacture of a medicament for treatment of tissue lesions.
The present invention finds application particularly in pharmaceutical and veterinary fields.
In the description below, references in parentheses () refer to the list of references presented at the end of the text.
State of the art The implantation of cells, tissues or organs for therapeutics is a major issue in medicine. Many works over a century have demonstrated the therapeutic benefits of these implantations in multiple applications and many techniques have made it possible to control and improve the quality of withdrawals, their conservation and preservation, or their expansion before implant them or reintroduce them to the recipient patient. Similarly many improvements have been made to performance and properties of the organs, tissues or cells that are used in processes, devices and products to bring after a reintroduction in the recipient patient a therapeutic benefit. Finally a better knowledge and mastery of adverse reactions sometimes associated with this reintroduction has also helped to ensure greater success.

2 However, after administration of the cells, the yields regarding their integration and / or therapeutic efficacy in view of the number of administered cells remains very low, thus implying the need for repeated treatment and very high treatment costs. In In addition, the low yields and significant costs limit the pathologies and / or patients likely to be treated by these methods.
There is therefore a real need in the state of the art to be able to further improve these processes and / or the biological tools used to optimize their use and expand the therapeutic field application.
There are in the state of the art compounds to improve the tissue environment. For example, polymers HBGFPP for Heparan Binding Growth Factors Protectors Potentiators), these HBGFPPs were defined by their property to protect the growth factors with affinity for heparin (such as FGF, TGFb and others), against degradation by proteases as well as than to potentiate the activity of these factors without presenting activity significant anticoagulant at the doses used. These HBGFPP
had surprising properties on the repair of muscle tissues, nervous, digestive tract tissues as well as a activity on the inflammatory reaction, as illustrated in particular by International Application W01995026739 or in the US Patent US7998922. These polymers have also been chemically defined and illustrated as tissue regenerative agents in models preclinical lesions of cutaneous, bone, corneal and ischaemia. They have also demonstrated anti-fibrotic effects, unique capabilities to protect against the effects of oxidative stress in models of ischemia, protective effects against aging and neurodegeneration and generally they promote regeneration process. A particular form of HBGFPP, RGTA, have demonstrated, during their use, an acceleration and improvement of

3 repair of tissue lesions such as skin, cornea, bone or the muscle ; and possibly a decrease in scarring and more generally fibroses (see review Van Neck et al., Heparan Sulfate Proteoglycan Mimetics Promote Tissue Regeneration: An Overview chapter 4 in Tissue Regeneration ¨ From Basic Biology to Clinical ISBN 978-953-51-0387-5, edited by Jamie Davies). The RGTA are also known to protect against deleterious effects due to irradiation (Mangoni M et al., J. Radiation Oncology Biol.
Phys. 2009,74,1242-1250), oxidative stress in lesion cases caused by irradiation (Yue XL et al, Eye Death and Differentiation 2009, 1-12), oxidative stress during ischemia (Desgranges et al .;
FASEB J. 1999 Apr; 13 (6): 761-6.) Or also in the case of tissue aging (Larramendy-Gozalo C, D, et al J Gen Virol 2007, 88: 1062-7).
In another therapeutic area, other effects of RGTA have has also been observed, particularly in the treatment of pain and itching and for which the person skilled in the art could not foresee a link with the process of repair or tissue regeneration since the effect was very fast and therefore independent of the repair process or regeneration much longer to operate.
RGTAs have been described and used to repair damaged tissues via including the protection of growth and communications cells on the site of injury and the recruitment of existing cells in the treated patient. For example, publications have showed an effect of RGTA on the mobilization of endogenous cells strains such as hematopoietic progenitor cells, or stem cells derived from blood (Albanes et al., Experimental Hematology 2009; 37: 1072-1083) or on growth, clonogenicity, migration and / or differentiation of mesenchymal stem cells in in vitro or in vivo.

4 The use of RGTA comprising benzylamine with bone marrow cells was considered in the application WO 2003101201 for treating infarction of myocardium to increase vascularization formation of collateral. However, this disclosure does not include any experimentation, nor any scientific results. Thus, the elements included in this document do not allow the reproduction of described or to consider any treatment. In particular, the Mullanghi et al., (Coronary, 22: 71) report that the RGTA co-injected with the mesenchymal cells taken on the same day of the bone marrow and directly injected into the infarcted area after ligation of the descending coronary at the Baboon does not have more functional efficacy that the RGTA injected alone into this muscle, reproducing the observations of Yamauchi H et al., FASEB J. 2000 (14): 2133-4, which showed that the RGTA alone had a strong ability improvement of recovery after myocardial infarction. The co-injection of cells and RGTA does not bring any beneficial effect additional information concerning recovery from post-myocardial infarction compared to the use of RGTA alone. In other words, no effect additional benefit has been observed / demonstrated by injecting cells and RGTA.
The literature also reports many studies of therapies to implant by different methods different origins and natures in order to recolonize tissue areas injured or impaired functions. Of all these studies, it appears a very great difficulty in obtaining survival of cells implanted in the area targeted, even more difficult is to obtain a colonization of space and more recovery in the duration of the functions of the organ or tissue having been thus recolonized. This problem is still a real problem challenge that is not yet solved satisfactorily.

There is therefore a real need to find a new compound and / or a process which can improve the treatment of tissue lesions and / or the effectiveness of cell therapies.
The use of RGTA mixed with a bone substitute biomaterial is

Described in the prior art (Billy et al., US Patent 2006/0257449). This document also considers the association of this biomaterials (tricalcium), with stem cells not RGTA, to try to promote implantation and colonization of the bone substitute, however without any explanation or description of the possible implementation work, step etc. Moreover, this disclosure does not include any experimentation, nor any scientific results. Thus, the elements described in this document and its teaching do not allow the reproduction or the development of any association between a bone substitute biomaterial and cells, nor any use of any association.
Many pathologies, particularly due to aging, include tissue degeneration phenomena and / or cell, for example Alzheimer's disease, degeneration macular, and / or caused by biological phenomena such as decreased oxygenation of tissues / cells etc.
For these conditions, and as mentioned above, there is a great need in the state of the art to find treatments effective, and / or in particular to improve existing treatments, particular regarding cell therapies.
There are also many genetic pathologies particularly involving tissue malfunctions and / or cells for which treatment is almost non-existent or little effective. For these pathologies, a treatment route consists of cell therapy. However, the effectiveness of these therapies is cause, in particular because of the weak cellular implantation after injection and / or the very high costs of these treatments.

6 There is therefore a real need to find a new composition, treatment to treat tissue lesions whatever their origin and / or increase the effectiveness of treatment of the compositions known and / or cellular therapies while decreasing their cost.
Description of the invention The present invention is specifically intended to meet these needs by providing a pharmaceutical composition for its application as a medicine for the prevention and / or treatment of tissue lesions said composition comprising a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group -R1000R2 or ¨R9 (C = O) R10, Y represents an O- or N-sulphonate group and corresponding to one following formulas ¨R30S03R4, -R5NSO3R6, ¨R7S03R8 in which :
R1, R3, R5 and R9 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and which optionally contains one or more aromatic rings, R2, R4, R6 and R8 independently represent a hydrogen atom or a cation, R7 and R10 independently represents a bond, a chain aliphatic hydrocarbon, optionally branched and / or unsaturated, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and a eukaryotic cell.

7 Advantageously, the inventors have demonstrated surprising and contrary to the teachings of the state of the art that the combination of biocompatible polymers of general formula (I) such as defined above, also referred to herein as RGTA, and cells allows both to prepare or condition the tissues and organs, receiving patient, to promote implantation, expansion and colonization of external cells and / or organ transplants and / or tissues, for example in the recipient patient.
In particular, the inventors have demonstrated surprisingly that the use of biocompatible polymers of general formula (I) combined with cells, organs, platelet extracts allows advantageously and surprisingly to significantly improve the recovery of the altered functions of the tissues and / or organs thus treated for the benefit of the patient.
In addition, the inventors have demonstrated that the combination of biocompatible polymers of general formula (I) with cells according to the invention can be used / applied for a large number of pathology / lesions etc. Indeed, the present invention finds a application regardless of the tissues or organs injured / implanted or grafted, whatever the cells used, for example injected, by example alone or in combination for example with lysates platelets for example enriched with growth factors or by example with injection of purified growth factors, including growth factors with an affinity for RGTAs or for heparan sulphates.
The inventors have also demonstrated surprisingly that the effect obtained on the functional recovery of the treated tissue is greater than the effect obtained separately either by the RGTA alone or by cells alone or by tissue or organ or biomaterials or lysates WO 2016/18908

8 platelets or pure growth factors implanted or injected alone.
The inventors have also demonstrated surprisingly and unexpectedly that the dosage, therapeutic regimen of administration of the composition advantageously makes it possible to optimize the effects therapeutics and furthermore has a strong synergistic effect observed in functional and cicatricial recovery of treated tissues or organs.
The results observed are all the more unexpected as the cells used according to the invention may have properties and origins different from those cells present in the tissues or organs in which they are likely to be implanted. In a way surprisingly, the composition according to the invention favors the colonization of implanted cells to the point, for example to rebuild a tissue or organ again functional despite the fact that these implanted cells may be of a different phenotype and tissue origin. In addition, without the need to experimentally induce the emergence of pluripotent stem cells or already engaged in the path of differentiation of the cells of the tissue or organ to be colonized.
The inventors have surprisingly demonstrated that the use of the RGTA according to the invention makes it possible to obtain an effect new and unexpected technical / therapeutic conditioning of the site lesionnel by the preparation of the ground implantation and to obtain cell implantation / efficacy of Therapeutic treatment far superior to that obtained during use of RGTA alone and / or that of the cells used alone, in particular concerning the effectiveness of the cellular treatment and / or the capacity implantation of cells or tissues or organs.
Thus, the inventors have demonstrated surprisingly and unexpectedly that the present invention, via for example the administration sequentially, that is to say according to a posology / dosage regimen, RGTA followed after a certain period of time, for example a few minutes

9 a few days, by the administration of cells of all kinds and / or chosen originals allows advantageously to favor in a way unexpectedly taking these grafts or the functional implantation of these few cells in origin, their stage of development and the mode preparation subject to checking, where appropriate, the aspects of rejection related to the immune system of the recipient.
In addition, the inventors have demonstrated, in particular in examples, that the application of the present invention, in particular the lesions that can be treated by the composition according to the invention can be to all types of tissue lesions regardless of their origin and has any type of tissue or organ. In particular, the skilled person, in the light examples below in which a wide variety of lesions are effectively treated, understand easily and can, in the light of these knowledge extrapolate other tissue lesions likely to be treated by the present invention.
In the present case, tissue lesions are understood to mean any lesion of any biological tissue of a mammal known to those skilled in the art. he can for example, connective tissue injury, muscle tissue, nerve tissue, bone tissue, cartilage and / or epithelial tissue. he can be for example any lesion of any organ, organelle of mammal known to those skilled in the art. It can be for example a lesion of tissues of the digestive tract, tissues of the gastrointestinal tract, of digestive system feeding and excretion, genital tract, system reproductive system, the optical, olfactory or auditory system, the sensory system, of the circulatory and / or cardiovascular system, the respiratory system, the muscular system, the locomotor system. It may be for example gastric tissue lesion, oral lesion, lesion of the cornea, tympanic lesion, lesion of the cochlea, lesion of the skin, for example a wound, a chronic wound, for example a diabetic wound, an ulcerous wound, an eschar, a cutaneous burn, necrotizing wound, venous lesion, ischemic injury, example ischemic necrosis, an injury due to an infarction, example a myocardial infarction, a bone lesion, for example a fracture, fracture with bone defect, osteonecrosis (non union bone fracture), an osteochondral lesion, a cartilaginous lesion, a Tendinous lesion, surgical lesion, lesion due to surgery surgery, an injury due to medical treatment, such as radiotherapy, a nerve tissue lesion, for example a lesion of the brain, for example a lesion due to excision of a tumor, spinal cord injury, a nerve fiber lesion, for example

10 locomotor and / or sensory system, a lesion of the respiratory system, for example pulmonary lesions, a lesion of the circulatory system, for example, arterial and / or vessel injury, lesion renal digestive system, urinary.
In the present case, for example, by monomer is meant for example a monomer selected from the group consisting of sugars, esters, alcohols, amino acids or nucleotides.
In the present, the monomers A constitute the basic elements polymers of formula I may be the same or different.
In the present, the combination of monomers can make it possible to form a polymeric backbone, for example a polymeric backbone of nature polyester, polyalcohol, polysaccharide, acid type nucleic acids or proteins.
Here, among the polyesters, it may be for example biosynthesis copolymers or chemical synthesis, for example aliphatic or naturally occurring polyesters, for example polyhydroxyalconaotes.
In the present, polysaccharides and their derivatives can be bacterial, animal, fungal and / or plant origin. he can for example, single-chain polysaccharides, for example polyglucoses, for example dextran, cellulose, beta glucan, or other monomers comprising more complex units, for example

11 xanthans, for example glucose, mannose and glucuronic acid or still glucuronans and glucoglucuronan.
In the present, polysaccharides of plant origin can be single chain, for example cellulose (glucose), pectins (acidic galacturonic acid), fucans, starch or more complex alginates (galuronic acid and mannuronic acid), In the present, polysaccharides of fungal origin can be for example, steroglucan.
Herein, polysaccharides of animal origin can be for example chitin or chitosan (glucosamine).
The number of monomers A defined in formula (I) by a can be such that the mass of said polymers of formula (I) is greater than about 2000 daltons (corresponding to 10 glucose monomers). The number of monomers A defined in formula (I) by a may be such that the mass of said polymers of formula (I) is less than about 2000000 daltons (which corresponds to 10000 monomers of glucose). Of advantageously, the mass of said polymers of formula (I) can be from 2 to 100 kdaltons.
Herein, in the group -Ri000R2 representing X, Ri may be C 1-6 alkyl, for example methyl, ethyl, butyl, a propyl, a pentyl, preferably a methyl group, and R2 may be a bond, a C1 to C6 alkyl, for example a methyl, an ethyl, a butyl, a propyl, a pentyl, a group R21R22 in which R21 is a anion and R22 a cation selected from the group of alkali metals.
Preferably, the group X is the group of formula -Ri000R2 wherein R1 is a methyl group ¨0H2- and R2 a group R21R22 in which R21 is an anion and R22 a chosen cation in the group of alkali metals, preferably the group X is a group of formula ¨0H2-000-.
Herein, in the group ¨R9 (C = O) R10 representing X, R 9 may be C 1-6 alkyl, for example methyl, ethyl,

12 butyl, a propyl, a pentyl, preferably a methyl group, and Rio may be a bond, a C1 to C6 alkyl, for example a methyl, a ethyl, butyl, propyl, pentyl, hexyl.
In this case, in the group meeting one of the following formulas ¨R30S03R4, -R5NSO3R6, ¨R7S03R8 and representing the Y group, R3 may be a bond, a C1 to C6 alkyl, for example methyl, ethyl, butyl, propyl, pentyl, preferably methyl group, R5 may be a bond, C1-C6 alkyl, by example a methyl, an ethyl, a butyl, a propyl, a pentyl, preferably a methyl group, R7 may be a bond, a C1-C6 alkyl, by example a methyl, an ethyl, a butyl, a propyl, a pentyl, preferably a methyl group, R4, R6 and R8 can be independently a hydrogen atom or an M + cation, for example M + may be a metal alkaline.
Preferably, the group Y is the group of formula ¨R7S03R8 wherein R7 is a bond and R8 is a selected alkali metal in the group comprising lithium, sodium, potassium, rubidium and cesium, Preferably, the group Y is a group ¨SO 3 -Na +
The degree of substitution of all the monomers A by the Y moieties defined in the general formula (I) by y may be from 30 to 150%, and preferably of the order of 100%.
Herein, the definition of the substitution rates above, means a substitution rate x of 100%, the fact that each monomer A of the polymer of the invention contains statistically a grouping X. Similarly, a substitution rate y of 100%, the fact that each monomer of the polymer of the invention contains statistically a group Y. The substitution rates greater than 100% reflect the fact that each monomer carries statistically more a group of the type considered; conversely, substitution rates less than 100% reflect the fact that each monomer statistically less than one group of the type considered.

13 The polymers may also include groups Functional Chemicals, designated Z, different from X and Y.
In this case, the Z moieties may be the same or different, and can independently be selected from the group comprising amino acids, fatty acids, fatty alcohols, ceramides, or derivatives thereof, or nucleotide sequences of addressing.
Z groups can also be active agents identical or different. It may be, for example, therapeutic agents, diagnostic agents, an anti-inflammatory, an antimicrobial, a antibiotic, a growth factor, an enzyme.
Herein, the group Z can advantageously be a saturated or unsaturated fatty acid. It can be for example a fatty acid selected from the group consisting of acetic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, acid lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaïclic acid, trans-vaccines, linoleic acid, linolenic acid, the acid linolenic γ-linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, eicosapentaenoic acid, clupanodonic acid or acid Docosahexaenoic. Preferably, the fatty acid is acetic acid.
Herein, the group Z can advantageously be a amino acid of the L or D series selected from the group comprising alanine, asparagine, an aromatic chain, for example tyrosine, phenylalanine, tryptophan, thyroxine or histidine.
Advantageously, the groups Z may confer on the polymers of biological or physicochemical properties additional. For example Z groupings can increase the solubility or lipophilicity of said polymer allowing for example a better diffusion or tissue penetration.

14 Polymers in which Z is present correspond to formula II
next :
Aa Xx Yy Zz wherein, A, X, Y, a, x, y are as defined above and z represents the substitution rate by Z groups.
Herein the substitution rate by Z groups represented by z can be from 0 to 50%, preferably equal to 30%.
The groups X, Y and Z can be independently fixed on the monomer A and / or independently attached to each other. When, minus one of the groups X, Y and Z is independently set on a group X, Y and Z different from the first, one of said groups X, Y or Z is attached to monomer A.
Thus, Z moieties can be covalently attached directly to the monomers A or covalently attached to the groups X and / or Y.
In the present, the composition may include a concentration from 0.01 microgram to 100 mg by weight of biocompatible polymer per relative to the total weight of the composition. For example the composition can to include from 10 micrograms to 10 milligrams by weight relative to the total weight of the composition.
In the present, the composition can be formulated and / or adapted according to his administration. For example, for a route administration intravenous or intramuscularly the composition may be administered in order to deliver a dose of biocompatible polymer included 0.1 to 5 mg per kilogram of body weight, or for one oral administration the composition may be administered by example in 2 to 5 equal sockets per day to a daily total per example of 1 to 500 mg, for example 10 microg at 5 mg per kg of biocompatible polymer, for example from 10 microg to 5 mg per kg, per example for an adult of 100 kg of body mass for several days to several weeks. For example, for a route administration intracranial, it may be a single administration of 1 to 5 mL, or by minipump over several days, the composition may include a Concentration of 0.001 to 1 mg.mL-1 of biocompatible polymer, or for an administration, for example daily from 1 to 5 mL, per sublingual composition may include a concentration of 0.1 to 100 mg.mL-1 of biocompatible polymer, or by air composition may be administered in order to deliver a dose of 0.1 to 5 mg of biocompatible polymer per kilogram of body weight said polymer.
For example, for oral administration, the polymer may be in solution, for example in water or in any suitable solvent for oral administration known to those skilled in the art. The

15 composition may also be in cachet, capsule or any other form compatible with an oral intake known to those skilled in the art. he can be an aqueous solution with a volume of 10 to 50 mL including example a concentration of 0.1mg.mL-1 of polymer in the solution.
For example, for systemic administration, the polymer may for example be in solution in physiological saline, for example example of injectable quality saline or any other form compatible with the injection, for example solutions with glucose and / or other suitable excipients known to those skilled in the art, by example comprising polysaccharides, for example heparin. By For example, the polymer may be at a concentration of 0.1 to 5 mg.kg-1, preferences from 1 to 2.5 mg.kg-1, for example for administration by Intravenous (IV) and / or intra-muscular (IM).
According to the invention, the composition may further comprise growth factors. It can be any known growth factor of the skilled person likely to promote, stimulate growth cellular. These may include, for example, growth factors selected from

16 the group comprising fibroblast growth factor (FGF), by example FGF1 or FGF2, vascular growth factor endothelial (VEGF), platelet-derived growth factor (PGDF) or a mixture thereof. According to the invention, the composition may from 10 nanog.mL-1 to 100 microg.mL-1 from growth.
According to the invention, the composition may furthermore comprise an extract or platelet lysate crude or enriched in growth factors. he can be for example any extract or platelet lysate known to the human profession and / or commercially available.
In the present per eukaryotic cell is meant any cell eukaryote known to those skilled in the art. It can be for example a eukaryotic mammalian cell, for example a eukaryotic cell animal or human. It can be for example any eukaryotic cell whatever its stage of differentiation, for example a chosen cell in the group comprising adult eukaryotic cells or embryonic, embryonic stem cells, stem cells adults. It can be for example eukaryotic cells of blood of cord, bone marrow cells, adipose tissue cells, mesenchymal cells. It can also be a group of cells, a graft and / or an organ.
This may be, for example, a heterologous, homologous or autologous of an individual. Preferably, the cells are cells Autologous.
It may also be a pluripotent or totipotent stem cell, or of cells involved in differentiation pathways, for example mesenchymal stem cells. It can also be a cell multi or totipotent strain with the exception of stem cells Embryonic.
Advantageously, when the cells are autologous, the composition according to the invention the present invention may be preferred for

17 regulatory, safety, feasibility, efficiency and economic.
Advantageously, when the cells are autologous, they are of preferably isolated from the individual and used in the composition according to the invention and / or used in a treatment within 24 hours after collection and isolation without further additions. Advantageously, this single administration makes it possible to overcome and comply with regulatory requirements / constraints.
In the present the quantity of cells included in the composition can be from 1 to 5x107 cells.
Advantageously, the inventors have demonstrated that the treatment is independent of the cell type, its origin, the means used to select, amplify, condition and modify the cells. In particular, the inventors have surprisingly demonstrated that this invention therefore applies to all cells whatever their provenances and manipulations of selections leading to engaging cells in differentiation or dedifferentiation pathways in the the extent to which the administration of the RGTA advantageously allows, in particular when associated with cell administration, the creation / formation of a microenvironment adapted to the cell allowing advantageously a synergistic cooperation between the RGTA and the cells to increase cell implantation.
According to the invention, when the composition comprises a graft or a transplant organ, or an implantable material the administration of the polymer and graft or organ or implantable material can be simultaneously. For example, the organ to be grafted or the implantable material can be impregnated, for example by immersing him in a solution comprising the biopolymer, either by infusion or by spray or any other adapted method known to those skilled in the art. In the case of material implantable, the polymer can be incorporated as soon as the material is made

18 implantable advantageously allowing preincubation or impregnation.
According to the invention, the duration of impregnation can be from a few minutes to several hours, for example from 1 to 18 minutes hours, from 5 minutes to 4 pm one night.
Advantageously, when the graft or organ is impregnated for a duration greater than 5 minutes, for example 16 hours impregnation also improves the efficiency of engraftment. In Indeed, the inventors have surprisingly shown that the presence of the polymer in the graft and / or organ preservation solution advantageously has a protective and anti-apoptotic effect.
Advantageously, the graft, the organ or the material impregnated with polymer may receive before or after reimplantation or transplantation administration of growth factors or platelet extract in order to promote colonization by the cells administered at the time of implantation or after.
In the present, by pharmaceutical composition is meant any form of pharmaceutical composition known to humans job. In the present, the pharmaceutical composition can be by example an injectable solution, for example for a local injection or systemic, for example in physiological saline, in glucose solution injectable, in the presence of excipients, for example Dextrans, by example at concentrations known to those skilled in the art, for example from microgram to a few milligrams per mL.
The pharmaceutical composition may be for example a medicament for oral administration selected from the group comprising a liquid formulation, an effervescent dosage form Oral Powder, Oral Powder, Multiparticulate System, Galenic Form orodispersible.
For example, when the pharmaceutical composition is for oral administration, it can be in the form of a liquid formulation

19 selected from the group comprising a solution, a syrup, a suspension, an emulsion. When the pharmaceutical composition is in the form of an oral effervescent dosage form, it may be in a form selected from the group consisting of tablets, granules, powders. When the pharmaceutical composition is in the form of a oral powder or a multiparticulate system, it can be in a form selected from the group consisting of beads, granules, mini-tablets and microgranules. When the pharmaceutical composition is in the form of an orodispersible dosage form, it can be in a form selected from the group consisting of tablets orodispersibles, freeze-dried wafers, thin films, one tablet chew, a tablet, a capsule or a medical eraser to to chew.
According to the present invention, the pharmaceutical composition can be a pharmaceutical composition for oral administration, by example oral and / or sublingual, for example chosen from the group including oral or sublingual tablets, lozenges, drops, a solution for spraying.
According to the present invention, the pharmaceutical composition can be a pharmaceutical composition for topical administration, transdermal, for example selected from the group consisting of ointments, creams, gels, lotions, patches and mousses.
According to the present invention, the pharmaceutical composition can be a pharmaceutical composition for nasal administration, for example selected from the group consisting of nasal drops, nasal spray, nasal powder.
According to the present invention, the pharmaceutical composition can be a pharmaceutical composition for parenteral administration, subcutaneous, intramuscular, intravenous, intrathecal example.
The composition of the present invention may also include at least one other active ingredient, particularly another ingredient therapeutically active, for example for simultaneous use, separated or spread in time according to the pharmaceutical formulation used.
This other ingredient may be for example an active ingredient used by example in the treatment of opportunistic diseases that may occur 5 develop in a patient with tissue injury.
In the present, the administration of the biocompatible polymer and the cell can be simultaneous, successive or concomitant.
According to the invention, at least one of the administrations can be realized oral or by injection. Both administrations may be 10 performed in the same way or differently. For example, administration of the biocompatible polymer and cells can be done by injection, administration of the biocompatible polymer may be by Oral and cells can be made by local injection. administration may also be a function of the site of the lesion.
15 According to the invention, the use of eukaryotic cells, in particular their administration can be carried out within 5 minutes to 1 a one week after the first administration of said biocompatible polymer.
In the case of tissue transplantation, organs or the use of implantable materials pre-impregnated with the polymer, the administration of

20 cell can be done before implantation or just after, by example in time.
According to the invention, the composition can be, for example, administered daily, twice daily and weekly. It could be for example, once a day, twice a day, or more.
According to the invention, the composition can be, for example, administered over a period of 1 day to 3 months, for example for 2 months. By for example, the composition can be administered over a period of 3 months with a frequency of administration every 15 days.
According to the invention, the biopolymer can be, for example, administered over a period of 1 day to 3 months, for example for 2 months, with

21 example a frequency of 1 time per day and the eukaryotic cell administered over the same or different duration, for example a duration from 1 day to 3 months, with a weekly frequency.
According to the invention, when the administration of polymers and cells are successive, the dosage for each administration may be a polymer administration followed by the administration of cells. For example, the cells can be administered from 1 minute to 24 hours after the administration of the polymers, from 30 minutes to 12 hours after polymer administration, 45 minutes to 6 hours after administration of the polymers, 1 hour after administration of the polymers.
According to the invention, the composition may furthermore comprise an extract platelet. It may be for example any platelet extract known from those skilled in the art adapted to be administered to a mammal. he can for example, a commercially available platelet extract, of a platelet extract obtained according to the process described in document D
R Knighton, et al., Ann Surg. Sep 1986; 204 (3): 322-330 Classification and treatment of chronic nonhealing wounds. Successful treatment with autologous platelet-derived wound healing factors (PDWHF) or in Everts papers, PAM et al., Autologous platelet gel growth factor release and leukocyte kinetics using three devices. Trans. Med., 2006, 16 (5), 363-368 or Is Use of Autologous Platelet-Rich Plasma Gels in Gynecologic, Cardiac, and General, Reconstructive Surgery Beneficial? "
Pharmaceutical Biotechnology, 2012, Vol. 13N 13). It can be extract Platelet corresponding to platelet lysates enriched in activity growth factor administrable, for example by local route, injectable or deposited in various media, for example in or on gels, creams, sprays and / or in damaged tissues. According to the invention, the extract platelet can be an autologous or heterologous extract of an individual to treat. Preferably, the platelet extract is an autologous extract. he can for example, an extract and / or concentrated platelet lysate, for example

22 example by methods and / or kits known to those skilled in the art and / or commercially available.
According to the invention, the composition may comprise from 0.1mL to 100mL
of extract and / or platelet lysate.
Advantageously, the platelet extract comprises growth promoting the creation of an environment conducive to cell implantation. These factors can be added to the excerpt platelet or used alone without extracts. According to the invention the factor FGF1 or FGF2 or VEGF or TGFbeta1 or BMP or other factors of growths, preferably at least one factor selected from the group including factor FGF1 or FGF2 or VEGF or TGFbeta1 or BMP
can be added. According to the invention, the factors included in the extract platelet may be added at concentrations of 10 ng to 100 microg / ml extract.
According to the invention, prior to the administration of the composition, the damaged tissue can be reactivated for example by reopening the lesion, scratching or mechanical scalpel debridement. Reactivation can be used, for example, on old wounds, for example consolidated bone fractures, old scars or chronic wounds.
The present invention also relates to a composition pharmaceutical or dermatological for its application as drug for the prevention and / or treatment of tissue lesions, said composition comprising a biopolymer of formula AaXxYy or AaXxYyZz and at least one platelet extract.
According to the invention, the platelet extract is as defined above.
According to the invention, the biopolymer of formula AaXxYy or AaXxYyZz is as defined above.
According to the invention, the pharmaceutical or dermatological composition is as defined above.

23 According to the invention the frequency of administration of the polymer biocompatible can be as defined above.
According to the invention, the mode and / or the route of administration of the polymer biocompatible may be as defined above.
The present invention also relates to a composition pharmaceutical or dermatological for its application as drug for the prevention and / or treatment of tissue lesions, said composition comprising a biopolymer of formula AaXxYy or AaXxYyZz and at least one growth factor.
According to the invention, the growth factor is as defined above.
According to the invention, the biopolymer of formula AaXxYy or AaXxYyZz is such as defined above.
The pharmaceutical or dermatological composition is such that defined above.
According to the invention the frequency of administration of the polymer biocompatible can be as defined above.
According to the invention, the mode and / or the route of administration of the polymer biocompatible may be as defined above.
The present invention also relates to a method of treatment of a patient having suffered tissue injury comprising in a any order the following steps:
i. administering at least one biocompatible polymer, and ii. administering at least one eukaryotic cell, in which the administrations are concomitant, successive or alternatives.
The biocompatible polymer is as defined above.
The eukaryotic cell is as defined above.
According to the invention, the patient can be any mammal. It could be for example an animal or a human being.

24 According to the invention, the eukaryotic cell administered can be a heterologous cell or homologue of said patient.
According to the invention, the mode and / or the route of administration of the polymer biocompatible may be as defined above.
According to the invention, the mode and / or the route of administration of the cell may be as defined above.
According to the invention the frequency of administration of the polymer biocompatible can be as defined above.
According to the invention the frequency of administration of the eukaryotic cell can be as defined above.
According to the invention, when the administration of polymers biocompatible and cells are successive, the dosage for each administration can be an administration of biocompatible polymers followed by the administration of the cells. For example, cells can be administered from 1 minute to 48 hours after administration of biocompatible polymers, 30 minutes to 12 hours after administration polymers, from 45 minutes to 6 hours after administration of the polymers, 1 hour after administration of the polymers.
Advantageously, the eukaryotic cell is an adult stem cell mesenchymal.
The present invention also relates to a method of treatment of a patient having suffered tissue injury comprising in a any order the following steps:
i. administering at least one biocompatible polymer, and ii. administering at least one extract and / or platelet lysate, in which the administrations are concomitant, successive or alternatives.
The biocompatible polymer is as defined above.
The extract and / or platelet lysate is as defined above.

According to the invention, the patient can be any mammal. It could be for example an animal or a human being.
According to the invention, the mode and / or the route of administration of the polymer biocompatible may be as defined above.
According to the invention the frequency of administration of the polymer biocompatible can be as defined above.
According to the invention, when the administration of polymers biocompatible and extract and / or platelet lysate are successive, the dosage for each administration may be an administration of 10 biocompatible polymers followed by the administration of the extract and / or lysate platelet. For example, the extract and / or platelet lysate may be administered immediately, that is, concomitantly, or minutes, preferably 10 minutes to a few hours, example from 1 minute to 120 minutes, preferably from 10 to 60 minutes After administration, for example, local or injection of polymers biocompatible, after several hours, preferably from 4h to 24h, by example after administration of the biocompatible polymer orally.
The present invention also relates to a method of Treatment of a patient having suffered tissue injury comprising in a any order the following steps:
i. administering at least one biocompatible polymer, and ii. administering at least one growth factor, in which the administrations are concomitant, successive or

25 alternatives.
The biocompatible polymer is as defined above.
The growth factor is as defined above.
According to the invention, the patient can be any mammal. It could be for example an animal or a human being.
According to the invention, the mode and / or the route of administration of the polymer biocompatible may be as defined above.

26 According to the invention the frequency of administration of the polymer biocompatible can be as defined above.
According to the invention, when the administration of polymers biocompatible and said at least one growth factor are successive doses, the dosage for each administration may be a administration of biocompatible polymers followed by administration said at least one growth factor. For example, said at least one growth factor can be administered immediately, ie from concomitantly, or for example from 1 minutes to a few hours, for example from 1 minute to 120 minutes, preferably from 10 to 60 minutes after administration for example, local or injection of biocompatible polymers, after several hours, preferably from 4h to 24h after administration of the biocompatible polymer orally.
In other words, even if in the present description it is done reference to a composition, it is clear that each of the compounds of the composition may be administered concomitantly with other compounds (eg in a single composition or in two compositions, each of these compositions comprising one or more components mentioned above, the mode of administration of each of the compounds or composition (s) which may be the same or different), or independently of one another, for example successively, by example independent administration of a biocompatible polymer and, independent administration of a eukaryotic cell, these administrations being performed on the same patient, concomitantly or successively or alternatively, in an order that is the one aforementioned or another order.
These different administrations can be carried out independently each other or in a related manner (composition or co-administration), by an identical or different mode of administration (injection, ingestion, topical application, etc.), one or more times a week, during one or several successive weeks or not.

27 The present invention also relates to a pharmaceutical kit for the prevention and / or treatment of tissue lesions comprising:
i.a biocompatible polymer, and ii. at least one eukaryotic cell.
The biocompatible polymer is as defined above.
The eukaryotic cell is as defined above.
The present invention also relates to a pharmaceutical kit for the prevention and / or treatment of tissue lesions comprising:
i.a biocompatible polymer, and ii. at least one extract and / or platelet lysate.
The biocompatible polymer is as defined above.
The extract and / or lysate is as defined above.
The present invention also relates to the use of a pharmaceutical composition comprising i.a biocompatible polymer, and ii. at least one growth factor for the manufacture of a medicament for the treatment of lesions tissue.
The biocompatible polymer is as defined above.
The growth factor is as defined above.
In this embodiment, by drug is meant a pharmaceutical composition as defined above.
Advantageously, the inventors have demonstrated that the administration sequential RGTA tracking after a certain time ranging from a few minutes to a few days of cells, whatever their natures and origins advantageously and unexpectedly to favor functional implantation of said cells or grafting. In Moreover, the inventors have also demonstrated that the aforementioned advantages

28 have also been observed some in origin, the stage of development and / or the mode of preparation of the cells used.
Advantageously, the invention thus provides a general answer and simple to a complex technical problem and for which a real need and persistent exists in the state of the art. It is illustrated in particular in a nonlimiting manner in the examples below easily extrapolate to those skilled in the art to all types of tissue lesions which that is the origin as well as any type of tissue or organ.
In particular, the inventors have demonstrated that the present invention can be generalized to all tissue lesions including share some common characteristics of tissue lesions comprising destruction of cells and extracellular matrix at level of the lesional site.
The present invention also relates to an ex-vivo process of transplant preparation comprising the impregnation of a graft and / or organ to be grafted into a solution comprising a biocompatible polymer.
The present invention also for the use of the biopolymer of formula AaXxYy or AaXxYyZz as defined above for the ex-vivo preparation of a graft and / or organ.
The biocompatible polymer is as defined above.
According to the invention, the impregnation can be carried out by any method known to those skilled in the art. It may be for example to plunge the organ and / or dipping it into a solution comprising the biopolymer, either by perfusion, either by spray.
The present invention also relates to the use of the biopolymer of formula AaXxYy or AaXxYyZz as defined above for the in-vitro and / or ex-vivo preparation of an implantable biomaterial.
For example, for implantable biomaterials, the polymer biocompatible can be added for example by impregnation after manufacture of the biomaterial, for example for a tissue or an organ. he can be for example also added during the manufacture of the biomaterial from the

29 starting, for example the biopolymer of formula AaXxYy or AaXxYyZz such as defined below can be added in successive layers by example similarly to 3D prints In the present, by implantable biomaterials have all implantable biomaterials known to those skilled in the art and / or available in the trade. It may be for example an implantable material compatible, for example of any kind, biodegradable, crosslinked or not, colonizable preferably. These may be biomaterials implantable to base for the crosslinking of proteins, for example collagen, fibrin, polysaccharides, for example dextran, chitin, hyaluronic acid, alginate, cellulose and their derivatives, of biodegradable copolymers and biocompatible based on glycolic acid, lactic, malic, polymers, for example can take liquid gel transitions by polymerization controllable by temperature, or by enzymes or irradiations or other processes. It may be for example polymer to polycaprolactone base, polyurethane, silicone polytetrafluoroethylene, inorganic salts, for example calcium phosphates or hydroxyapatite. It may be for example materials based or in ceramic, of metal, for example of aluminum, steel, titalen and / or alloys of these. Advantageously when the material is a base material or ceramic and / or metal, the impregnation allows covering the outer surface of the material, the impregnation can advantageously be carried out by spray.
According to the invention, the impregnating solution may comprise a 0.1microg.mL-1 concentration at 1 mg.mL-1 of biocompatible polymer such as defined above.
According to the invention, the duration of impregnation can be from minutes to 24 hours. Advantageously, the duration of impregnation can be function of graft structure and / or organ and / or material Implantable.

Advantageously, the impregnation also makes it possible to improve the effectiveness of engraftment. Indeed, the inventors have shown surprisingly that the presence of the polymer in the solution of preservation of the graft and / or the organ advantageously has a 5 protective and anti-apoptotic effect.
The impregnation can be advantageously completed, after impregnation with the biocompatible polymer by an impregnation of growth factors and / or platelet extracts as mentioned above.
above. According to the invention, the duration of impregnation of Growth and / or platelet extracts may be 5 minutes to 24 hours.
The impregnation can be advantageously completed by impregnation and / or ex-vivo and / or in-vitro deposition of cells on the implantable biomaterial impregnated with the biocompatible polymer.
According to the invention the cells are as defined above.
According to the invention, the solution of impregnation and / or deposition of cells can understand a concentration a few thousand to a few million cells, preferably 10,000 to 1,000,000 cells.
According to the invention, the duration of impregnation and / or ex-vivo deposition And / or in vitro cells may be from 5 minutes to 24 hours.
Herein, the impregnation and / or deposition of cells on the implantable biomaterial impregnated with the biocompatible polymer can be performed by any suitable method known to those skilled in the art.
In addition, according to the invention, the implantable biomaterial impregnation 25 can be advantageously completed, after the impregnation by the biocompatible polymer and / or impregnation or deposition ex-vivo and / or cells, by impregnation with at least one factor of growth.
According to the invention, the impregnation on the implantable biomaterial

Impregnated with at least one growth factor can be carried out by all adapted method known to those skilled in the art.

31 According to the invention, the growth factor is as defined above.
According to the invention, the impregnation solution of at least one growth may include a concentration of 10 ng / ml to 100 microg / ml growth factors.
According to the invention the platelet extract and / or platelet lysate is such as defined above. It may be for example a platelet extract concentrated, for example from 5 to 100m1 of blood via, for example, the use of platelet concentration kits known to the man of the and commercially available, for example the Curasan Kit (registered trademark), Plateltex (registered trademark), GPS (registered trademark) II
and RegenLab (registered trademark).
According to the invention, the impregnating solution may comprise a concentration of 0.1 to 6 ml of platelet extract.
Other advantages may still be apparent to those skilled in the art on reading the examples below, illustrated by the appended figures, given for illustrative purposes.
Examples Example 1: Preparation of RGTAs and Method of Administration The synthesis of RGTA is widely described in the prior art, for example in the patent entitled- SULFONATION PROCESS
OF COMPOUNDS COMPRISING HYDROXYL GROUPS
(OH) FREE OR PRIMARY OR SECONDARY AMINES AND
also in the bibliographic reference: Yasunori I. et al., Biomaterials 2011, 32: 769e776) and Petit E. et al. Biomacromolecules.
2004 Mar-Apr; 5 (2): 445-52.
In the examples below, several known and described RGTAs have been used including 0TR4120 (described in Khammari-Chebbi et al., J
Ophthalmol. 2008 May; 31 (5): 465-71) and the 0TR4131 (described in Frescaline G. et al., Tissue Eng Part A. 2013 Jul; 19 (13-14): 1641-53. doi:

32 10.1089 / ten.TEA.2012.0377) available commercially. In addition, the 0TR4131 compound is a compound comprising a radical Z which is a fatty acid, namely acetic acid described in Virginie Coudry, et al.
Long-Term Follow-up of Superficial Digital Flexor TendonitisTreated by a Single Intralesional Injection of a ReGeneraTing Agent in 51 Horses Journal of Equine Veterinary Science 34 (2014) 1357-1360 and a compound wherein Z is an amino acid such as phenylalanine described in US Patents 7,998,922 and US Patent 8,790,631 were also used in the examples below.
In the examples below, the administration was carried out as previously described. In other words when the RGTA is not not mixed in a single solution with the cells, this one has been administered according to the known modes of administration for this compound.
Advantageously, when the RGTA is administered via a independent composition one of the effects obtained can be a preparation the tissue or organ to be treated to promote implantation, colonization and expansion by selected cells allowing a repair and tissue regeneration more efficient and synergistic because of the combination RGTA and cells.
The frequency of administration may be single or repeated every weeks or fifteen days see monthly, rarely for a duration total of several months, depending on the success of colonization and required number of injection / administration of cells, the time necessary for the preparation of the niche before implantation.
The concentrations and doses of RGTA administered depended forms of local or systemic administration, frequencies, tissues, organs or areas to be treated, volumes or surface of the lesion.
In the examples below when the administration is performed orally, RGTA may be in solution in water or form of any other oral presentation but also in character, capsule or any other form compatible with oral intake. In addition,

33 advantageously, the orally administered RGTA present a resistance to degradation by acid and digestive juices remarkable. Advantageously, the product having no taste and perfectly soluble in water, the preferred setting is in the form of a aqueous solution in a volume of 10 to 25 mL and at a concentration 0.1mg.mL-1 so that the amount is 1 to 2.5 mg per dose, two to five times a day. In the majority of examples, these catches were morning on an empty stomach and at bedtime for patient weights ranging from 50 to 100 kg, the doses and frequencies may also vary, as well as overall daily intake was between 1 and 500mg / day. The duration of this administration can be of several months without any effects adversaries have been observed. In particular, an intake by an individual of 25 mg / day over more than one year did not cause any discomfort or effects apparent secondary.
In the case of treatment of the digestive tract with cells so to repair and regenerate lesions, the amounts of RGTA can be advantageously reduced. Indeed, RGTA molecules can advantageously go directly with the damaged tissue and, for example recreate a niche, advantageously allowing a better implantation of the cells and if necessary to promote their proliferation.
The doses used during treatment of the digestive tract may be, for example, example of 1 to 50 mL at 100 microg.mL-1 per day. It can be by example of doses identical or similar to those described in Meddahi et al., J Biomed Mater Res 60: 497-501 2002, by example for the treatment of gastric or digestive ulcers, identical or similar to that described in the document Alexakis et al., Gut 2004; 53: 85-90 for the treatment of Crohn's pathologies, or doses identical or similar to those described in the document Alexakis et al., FASEB J. 2001, 15, 1546-1554 for damaged tissues after irradiation.

34 In the examples below when the administration is performed by systemic injection, RGTAs were preferably in solution in physiological saline of injectable quality or any other form compatible with the injection, especially solutions with glucose or other usual excipients with polysaccharides such as heparin, or mixed with therapeutic products with other properties subject to having assessed the risk of interactions with other active subtances. RGTAs were used at concentrations of 0.1 to 5 mg.kg-1, preferably 1 to 2.5 mg.mL-1 intravenously (IV) or Intra-Muscular (IM). For this route of injection, it may be a single injection, daily or weekly.
In the examples below where possible local administration in or near the tissue or injured site been privileged. In particular, this route of administration has been favored for the mucous membranes, for example oral, vaginal, urethral, digestive system with endoscopic or vascular or cardiac access, and / or in areas of more difficult access but likely to be directly reachable like the spinal cord, the peri-retinal zone, ventricular, pulmonary airways or during surgery opening the direct access or directly through other tissues or organs with suitable catheters, needles or endoscopes.
RGTA can also be administered as a spray on a surface tissue in the case of implantations of single cells or in sheets or still impregnated in implanted materials support for a existing or future cell colonization.
Regarding the airways, the administration may be also considered by inhalation.
Regarding mucous membranes and / or walls of the digestive tract or uterine muscles or ligaments, the rectal or vaginal route has been preferred when accessible.

For the treatment of ocular tissues, the preferred form of administration was for example in eye drops, for example for the treatment of the cornea, by trans-corneal injection for example in the treatment of Decemet's membrane, in the treatment of tissues 5 lining the bottom of the eyeball, for example for the treatment of defects of vision, or for example for the treatment of lesion of hearing-related tissues, for example for cell implantation ciliary of the cochlea.
In the examples, local administration or injection can be 10 daily or weekly, the dose being then linked to the surface or volume of the lesion. In particular, in the examples the RGTA concentration was preferably 100 microg / mL being the preferred concentration and the volume used chosen to cover the damaged area or impregnate the volume of the lesion. Thus, the peri-In the tissue or organ or in the site 0.1 to 0.5 mL of RGTA allowed to impregnate a tissue in a volume of 5 to 100 times superior. In surface or spray application, penetrating RGTA
by adsorption, the recovery of the injured area was sufficient. So three to four sprays of 140 mL each at 5 cm distance 20 of the lesion were sufficient to impregnate an area of 10 cm 2, alternatively a few milliliters of a cream or gel or ointment may spread over or near the lesion and thus provide access to the RGTA. Galenic forms of creams, ointments, gels, milks, foams, emulsions, powder pastes, etc. are those known from Those skilled in the art and preferences selected for their properties hydrophilic and moisturizing agents compatible with polysaccharides by example Hyaluronic acid.
In the examples, another way of administering the RGTA used was that of impregnation of tissues, for example for the case of grafts 30 of tissue or organ such as kidney, liver, heart, lung, skin, cornea, tympanum, muscles, nerves, tendons, ligaments, bones, vessels or intestines, colonists both in the anastomotic areas and in implants, bladder, etc. without this list being exhaustive. In this mode of realization that can be used to all tissues or grafts, the organ to graft which can be impregnated, for example by plunging it into a RGTA solution, either by infusion or by spray or any other method known to those skilled in the art. advantageously, the impregnation of the tissues as mentioned above allows advantageously to recreate the tissue microenvironment. Indeed, advantageously RGTA specifically binds to heparan sites available after the injury and induced by the removal of the graft or recipient transplant preparation. advantageously this fixation allows to recreate a niche that favors colonization by cells. The preferred concentrations of RGTA were from 0.01 to 100 micrograms (mg) per mL. The duration of impregnation was short because a few minutes are enough. Advantageously, an impregnation of a few hours or day (s) can simplify the procedure because RGTA can be added to conservation solutions and prove to be as a protective and anti-apoptotic agent as described in the prior art (Barritault D., Caruelle JP, BIP121532, POLYMERS
BIOCOMPATIBLES, PROCESS FOR THEIR PREPARATION AND
COMPOSITIONS CONTAINING THEM; and Yue XL, Lehri S, Li P, Barbier-Chassefiere V, Small V, Huang QF, Albanese P, Barritault D, Caruelle JP, Papy-Garcia D and Morin C. Insights on a new path of pre-mitochondrial apoptosis regulation by a glycosaminoglycan mimetic .; Yue XL et al, Cell Death and Differentiation, 2009, 1-12). The tissues were then exposed to enriched solutions or suspensions where appropriate in cells of a desired specificity this before or after implantation. AT
this technique can be added extracts or platelet lysates enriched with growth factors.
Autologous cells were added with the front graft or after implantation, which advantageously facilitates the colonization of junction host junction sites and promote the taking of graft. This method allows a transplant, avoids necrosis and increases functional recovery.
In the examples, platelet extracts were administered only after administering RGTA or RGTA. In this case the mixture was made with ratio RGTA / PRP extract so lysate platelets obtained from 109 platelets suspended in 1 ml of physiological saline is placed in the presence of thrombin or at 100 mg RGTA. At the end of the degranulation of platelets the solution was centrifuged at low speed. The supernatant containing the factors Platelets and RGTA were then administered at the lesional site.
In another embodiment, single or mixed RGTAs with platelet extracts (PRP) or isolated factors were injected with the therapeutic cells.
In the examples, the administration of the RGTA was carried out at later at the time of the first administration of the cells, or preferably a few hours or days before. So in the case of taken oral reports of RGTA we observed that one or more daily one week before cell therapy was increasing the end result of tissue regeneration, the preferred dose then being drink 25 mL of RGTA 0TR4120 at 100 mg / mL on an empty stomach and in the evening before going to bed for at least a week. During an injection IV or local RGTA, cell therapy could be implemented from the hour following the administration of RGTA.
In the examples described below, the cells are autologous and preferably administered on the same day as that of their sample.
Example 2: Example of treatment of a tissue lesion with administration of RGTA and Stem Cells Mesenchymal (CSM) in a mouse model.

In this example, the mice used were 70 mice 10-week-old females (C57 / BL6) Charles River divided into 7 groups of 10 mice and correspond to a mouse model recognized in the state of the technique.
A cutaneous wound was made on the back of the mice using a die cutter 6 mm in diameter (used for biopsies in clinic) and the wound was then left in the open air. 4 wounds were performed on each animal.
The polymer used was 0TR4120 and was administered by injection subcutaneous (SC) at 25 microL (pL) of a 100 μL solution in two points (diametrically opposed). The stem cells Mesenchymal (CSM) from bone marrow (tibia) isolated according to classical protocols such as those described in A protocol for Isolation and culture of mesenchymal stem cells marrow, Soleimani M, Nadri S. Nat Protoc. 2009; 4 (1): 102-6, have been suspended in phosphate buffered saline PBS at a concentration of 1 X 106 cells per mL and injected at 2 injections of 50 μL per wound at two points (symmetrical orthogonal to those of the RGTA) at different times and the wound was then measured at 3,5,7,10 days after the injury.
During the experiments, for each mouse, several wounds were carried out and a comparison was made between:
- two injections diametrically opposed to the wound for the RGTA, - two injections diametrically opposed to the wound for MSCs, and - four injections at the 4 cardinal points coupling the RGTA and CSM
Different groups of mice have been defined according to the composition administered according to the aforementioned methods and are detailed below.
below:

- Group 1 Control (Placebo): Administration of Serum physiological within 15 minutes of wound / injury.
- Group 2 Administration of CSM: 1 million CSM per administration in 2 symmetrical points in opposition of the sites RGTA injection, 24 hours after the injury after the injury.
- Group 3: administration of RGTA after injury - Group 4: administration of RGTA mixed with CSM (co-injected) - Group 5: administration of RGTA after injury of CSM 5 minutes later.
- Group 6: administration of RGTA after injury CSM 6 hours later.
- Group 7: administration of RGTA after injury of CSM 12 hours later.
- Group 8: administration of RGTA after injury of CSM 24 hours later The table below summarizes the kinetic results wound closure measured in% on each animal according to the treatments. At zero time, the area of the lesion is by definition 100%
for each animal, when the wound is closed the value is 0%.
Table 1: evolution of the wound as a function of time Group / days 0 3 5 7 10 1-PBS 100 53 +/-15 29 +/- 15 15 +/- 10 5 +/- 5 2-CSM 100 38 +/- 10 20 +/- 5 10 +/- 5 0 3-RGTA 100 40 +/- 5 25 +/- 5 10 +/- 5 0 4-RGTA + CSM co-100-F1-5 +/- 8 +/- 5 0 injection 5-RGTA + CSM 5mn 100 38 +/- 5 20 +/- 5 8 +/- 5 0 6-RGTA + CSM 6h 100 30 +/- 5 15 +/- 5 5 +/- 5 0 7-RGTA + CSM 12h 100 15-F / -5 5-F / -5 0 0 8-RGTA + CSM 24h 100 10-F / -5 0 0 0 Table 1 shows that the administration of CSM and RGTA
allows to improve the tissue repair and in particular allows to significantly accelerate healing. In particular, administration Cells 24 hours after the RGTA allows closure of the wound which is much higher than that obtained with the RGTA alone or the CSM alone.
A comparable effect was obtained with cells from of mouse adipocytes of the same litter.
Examples of the invention observed in clinic Many examples made in clinic mentioned below illustrate the effects of the invention. The product RGTA in its form commercial 0TR4120 or CACIPLIQO being easily accessible. By cons, objectification is impossible and only clinical observations Document the effects of the invention.
Example 3 Effect of Treatment Combined with RGTA and Cells Autologous Mesenchymal Stem (CSM) in Healing chronic wounds.
In these examples, patients with different types of wounds chronic etiology varied as diabetic ulcers, venous, ischemic, pressure ulcers, burns and engraftments were therapeutic failure for months. Several treatments had been tried unsuccessfully including local treatment at CACIPLIQO (RGTA
0TR4120) according to the manufacturer's recommendations.
This clinician also used to combine the technology of RGTA with platelet extracts or to carry out therapies from autologous CSM obtained by sampling 5 mL
bone marrow of the sternum on the consenting patient. Sampling filtered and enriched by centrifugation according to the techniques described for the CSM were suspended in 1.5 mL of saline and the cell solution injected into the edges of the wound subcutaneously as well only in the center of the wound. In all a dozen injections of 0.1 mL
according to the perimeter of the ulcer (and according to the image assimilating the ulcer quadrant of a clock and injecting each position with hours).
According to this clinician, the only use is RGTA or therapy.
cell did not allow healing of the wound.
Combined administration according to the invention of RGTA and cells was also performed. CACIPLIQ has been applied locally according to the recommended protocol for the product CACIPLIQ:
solution of 5 mL to 100 μL of CACIPLIQ (RGTA 0TR4120) was on a compress of 15x15 cm and the impregnated compress was applied for 5 minutes on the well-cleaned wound and removed. MSCs have was then injected as described above (example 1) in the hour after the application of the RGTA. CACIPLIQ was then administered locally twice a week. For some patients a second bone marrow sample was taken 3 weeks later, and the patients were again treated as before by a injection of CSM. The result was very fast since the closure of all ulcers was observed in less than 6 weeks.
Another series of clinical trials was also conducted on other patients, by injection of CACIPLIQ (RGTA) and then injection of cells within the hour following their collection (the time to prepare the cells). The result was even more surprising since all patients were able to heal completely in less than a month. In addition, he even noted that some of these patients have seen their sore close in 15 days while it lasted for months without any sign of improvement. A
such rapidity had never been observed by this clinician, whatever the applied treatment, especially during treatment with CACIPLIQO alone or the CSMs alone.
This example clearly demonstrates that the composition according to the invention advantageously and surprisingly makes it possible to treat tissue lesions, including chronic wounds, and advantageously allows a significant acceleration of the cicatrization.
In addition, this example clearly demonstrates that the composition according to the invention provides a new solution to a problem for which no solution did not exist in the state of the art.
In addition, a similar or even better effect was observed on patients by co-administration of RGTA, PRP and cells.
In a preferred embodiment, the administration of RGTA has been followed by an injection of PRP and then cells, which administration was for regulatory reasons carried out in the same operating time.
RGTA was administered alone (1 mL to 100 mg / mL 0TR4120), with or without sequentially PRP (from platelet lysate from a blood sample of the patient for example 50 mL), with or sequentially autologous mesenchymal cells by for example, but not limited to, different tissue sources.
In another embodiment, a sample of cells mesenchymal strains was performed from the adipose tissue of the patient to be treated by liposuction. The process of isolating the CSMs was identical to the process described in Example 1 above In another example of treatment using the composition according to the invention, a patient having a deep wound covering a part the bottom of the foot including the big toe and comprising a visible necrosis on a good half of the underside of the toe. A smell strong decomposition filled the consultation room. A first treatment with a cell therapy by injections of 0, .1 mL into several points around the wound a total of 1 mL of mesenchymal cells directly from the bone marrow of the patient's sternum has been implemented unsuccessfully further the condition of the wound had worsened. A
second treatment using the administration of CACIPLIQ alone (brand locally) has also failed to improve the wound and has allowed only to avoid further degradation and maintain a status quo status on the evolution and worsening of the wound thus avoiding an immediate amputation. Following these failures, an injection of 0.5 mL
5 points from 0.1 microg.mL-1 to 100 microg.mL-1 from the RGTA (CACIPLIQ) at level of the junction of still healthy areas from that necrotic of the toe then one hour after 5 injections of 0.1 mL each of cells directly from a new sample of 0.5 mL of cells by puncture at the sternum level. Following the administration of the composition according to the invention a regression of the wound has been observed, to prevent amputation, including complete healing of the wound. In particular, the necrotic zone was totally eliminated then replaced by budding from the still healthy tissues and contiguous to the wound until complete recovery of the wound. In this example a single injection sequence (RGTA then autologous cells mesenchymal) was sufficient to treat this patient and allowed closure of his wound Example 4: Effect of combination treatment with RGTA and Cell therapy in the healing of bone tissue.
In this example, the treatment of a fracture with a union fault putting was carried out using the composition according to the invention.
Similarly, the prior art describes in A to know an association ineffective and dissuasive of RGTA administration with therapy cell has been realized in the state of the art but has not made it possible to obtain no improvement in fractures and these after several months. The results on open wounds allowed for acceleration remarkable scar process.

Patients with tibia fracture with bone defect (no union bone fracture) which has not been able to improve by application of RGTA alone or after administration of cells from bone marrow according to the protocols of the art described above or that described by (Hernigou P, Nomma Y, Flouzat-Lachaniette CH, Dagger A, Chevallier N, Rouard H. Cancer risk is not increased in patients treated for orthopedic autologous bone marrow cell concentrate. J Bone Joint Surg Am. 2013; 95: 2215-21).
Patients who did not respond to treatment with RGTA alone treatment with autologous cells taken directly from the bone marrow, were treated with the composition according to the invention. Of surprising and unexpected way, especially in the light of the teaching of the state of the art, the use of the composition according to the invention, in particular the combination of RGTA with the cells from the bone marrow allowed to start the scar process in these patients and to get what no treatment had managed alone, thus showing the interest of the invention. In particular, three patients in failure have been treated with the composition according to the invention and have been benefit from this double treatment. In these cases cells from bone marrow were administered 1h after administration of 1mL of RGTA by local injection in the none union zone and 1 mL of Mesenchymal cells, punctured from the patient's sternum and reinjected into the bone defect area without further steps of treatment.
A combination further comprising platelet extracts has It has also been practiced and gives excellent results during its use between the administration of RGTA and cells. In particular, of the very positive results were obtained during the administration of the RGTA, then one hour after PRP and then cells.

In this other example, the effect of the composition according to the invention on bone preservation and action on ischemic necrosis of the femur head were also studied. A treatment using the RGTA and cells or RGTA, PRP and cells were made. The 5 patients with ischemia cases from femur head to stadium early before the installation of deep necrosis and causing significant pain. Treatment using RGTA and cells according to the invention prevented the destruction of the femoral head and the need to perform surgical procedures in order to implement a 10 prosthesis. The treatment consisted of the local injection of 1 mL
RGTA
0TR4131 at 10 microg.mL-1 in the near perioperative ischemic zone lesion followed 30 minutes after the local injection of 5 mL of cells Autologous bone marrow derived from the iliac fossa during the day even.
In another case co-treatment with PRP was performed, the PRP was prepared from a 10 mL sample of blood peripheral according to the usual methods and injected locally a few minutes before the collection cells. The results obtained via these two treatments showed a preservation of the head of the femur. He is at Note that in many of these patients with necrosis tissues already installed, a total disappearance of the necrosis suggesting a process of regeneration and replacement of necrotic tissue. The combination of RGTA and autologous cells allows advantageously to obtain this regeneration with a synergistic effect and Surprising, improved by the injection of the PRP. In this example, the effect of the composition according to the invention in the treatment of bone destruction in the case of post-infection osteonecrosis has been studied.
The destruction of bone tissue is a frequent consequence and a complication of the treatment of chronic wounds following a Osteomyelitis of bacterial infectious origin normally treated in long-term antibiotic therapy. The composition / process according to the invention has been implemented and has saved and rebuilt bone tissue.
The synergistic action of RGTA complemented by cell therapy has allowed a regeneration of injured bone tissue as never observed with the RGTA alone nor cell therapy alone. Several patients treated in this way by several local injections of 0.1 mL of CACIPLIQ (0TR4120 to 100 microg.mL-1) in the healthy tissue part around the necrotic area followed by injection of the same volume of mesenchymal cells removed from the sternum of the patient without further preparation have thus allowed to recover bone tissue before complete destruction, which would have been impossible without this therapy. It should be noted that this treatment was done in antibiotic therapy and yet it has not been observed integral bone regrowth, the treatment to save recover but not an ex nihilo regrowth of a bone completely destroyed.
Example 4: Treatment of joint and tendon lesions with an exemplary composition according to the invention.
The prior art describes the effects of the injection of RGTA alone, including the 0TR4131 in the treatment of tendon lesions and joints in sport horses (Coudry V et al Journal of Equine Veterinary Science, 2014, 34 Pages 1357-1360, David Carnicer, Memory Preliminary report: ultrasonographic evolution of tendon treated with RGTA in horses national veterinary school of Maison Alfort), the same is true of the use of cell therapy, including mesenchymal cells taken from the horse at level of the iliac fossa or more commonly of the sternum (Pechayre M. and Betizeau C. S0704, AVAC Congress, 2-4 December 2011). Lyon congress annual.
PRP was also used in the same indications (Http://fr.slideshare.net/dvmfun/platelet-rich-plasma-prp-therapy) A comparative study was conducted using horses treated by combining RGTA and the cells according to the invention, the RGTA and PRP, RGTA, PRP and cell therapy versus treatment with only cells.
In this example the horses had either lesions tendonous (at SFD tendon level) or articular (osteochondrosis dissecans, subchondral bone cysts, meniscus lesions). In all cases the combined treatment RGTA and mesenchymal cells has allowed a much faster recovery of horses in the race (recovery at about 5-6 months is a gain of one to two months compared to recovery time after treatment with RGTA alone or treatment cell only). This recovery being evaluated at the level of recovery, a quicker return to training and previous performance for almost all treated horses. For these horses the RGTA was injected at first in the week following the tendon lesion under ultrasound. The injection of cells had depending on the case, the same day but after that of the RGTA (most often about 30 minutes to a time corresponding to the time required for cell preparation). The injection of RGTA has sometimes been followed minutes after injection of PRP and injection of cells Autologous.
The amounts of RGTA, cells and PRP were respectively 1 mL of 0TR4131, 1.5 mL of PRP lysate (from 10 mL of blood taken and 1 mL of autologous cells and administration PRP and cells being performed one hour after the first RGTA injection The best results were obtained in the case of lesions articular when the cells were injected mixed with a biomaterial, such as collagen or hyaluronic acid or a combination of both. In these cases these products are of quality injectable solution (used in plastic surgery for the wrinkle or joint in humans) were directly added to the solution of cells before injection. The cell solution is then diluted twice approximately 1 mL of cells and 1 mL of biomaterial solution preferably between 0.1 to 3 mg.mL-1 In another embodiment an administration in a bolus has was performed comprising either RGTA and cells or RGTA, PRP and cells.
The results obtained showed an effective treatment and significantly improve over a treatment involving the administration of a single aforementioned elements. Moreover, even more surprising results were obtained by spacing the administration of RGTA and cells from one duration of 30 to 60 minutes to a few hours (preferably the same).
Currently, the treatment of joint lesions and pain of patients is performed by cellular therapies and especially by the local injection of autologous mesenchymal cells from bone marrow or adipose tissue.
However, this treatment does not provide treatment effective and presents failures. Also, a treatment using the composition according to the invention, especially via the administration (injection) of RGTA in synovial fluid followed by cell injection autologous mesenchymal or adipocytes was performed at several patients failing cell therapy alone. To do this, the amounts of RGTA and cells were respectively 1 mL to 100 microg.mL-1, 1 to 5 mL of autologous cells enriched in cells mesenchymal adipocytes by centrifugation and injected during the day same, usually 30 minutes to one hour after the injection of RGTA. The injection timing of the cells was achieved within one hour following the injection of RGTA or an injection of two solutions, one of RGTA immediately followed by cell injection or administration simultaneous RGTA and cells via a single solution.
The addition of Hyaluronic acid after the injection of RGTA but before or with cell injection as well as combination with other biomaterials such as type 2 collagens have yielded further results better in some patients.

Following this treatment and surprisingly, the lesions and The associated suffering has been resorbed patients to walk again without needing implantation a prosthetic knee and without pain.
In particular, in about ten patients with lesions osteochondrals, very handicapped in their movements and by the pain, having previously been unsuccessfully treated with cells or with the RGTA alone. Following the aforementioned treatment, eight of them were able to recover a motor capacity thanks to the double treatment RGTA then autologous cells, clearly demonstrating the surprising benefits and unexpected of the composition according to the invention.
Example 5 Treatment of System Tissue Lesions digestive with a composition according to the invention The prior art describes the properties of RGTA on the mucous membranes of the digestive tract, buccal (Morvan et al., Am J Pathol 2004 Feb;
164 (2): 739-46), gingival (Escartin et al., FASEB J. 2003 Apr; 17 (6): 644-51), ulcerations in the stomach or intestines (Meddahi et al., J. Biomed Mater Res., 2002, 60 (3): 497-501); as well as their ability to reduce fibrosis by acting at the level of syntheses of collagen on isolated, normal or irradiated cells (Alexakis C. and al., FASEB J. 2001 Jul; 15 (9): 1546-54) as well as on biopsies from tissues of patients with Crohn's disease (Alexakis C. et al., Gut. 2004 Jan; 53 (1): 85-90). However, no effect of RGTAs on lesions of the tissues of the digestive system, in particular with regard to possible repair of lesions, has not been observed or identified.
In this example, a treatment using the composition according to the invention namely an RGTA and cells was applied to a patient suffering from Crohn's disease and suffering from a perineal fistula since several years. In this example, the RGTA used at a concentration 100 microg.mL-1 of 0.5 mL was injected near the fistula (0.1 mL

injection and at 3 sites) followed within 30 minutes of the injection of fraction enriched in cells from a 10 mL sample of liposuction) (0.1 mL per injection at two or three cell sites) The administration of the composition according to the invention has made it possible 5 close the perianal fistula while neither the RGTA alone nor the administration of these same cells had not made it possible to obtain this closure and healing.
A second patient having surgical removal of a squamous cell carcinoma very close to the sphincter followed by chemo-radiotherapy having lost the function of his sphincter could benefit Of a local injection of RGTA 0TR4120 (0.1mL at 100 microg.mL-1) into several sites followed after 30 minutes of a local injection of cells autologous adipocytes (100 microL / injection from an initial volume 10 mL liposuction). Following this administration a colonization rapid onset of lesion site cells was observed allowing the patient 15 a functional recovery of the sphincter which did not seem impossible.
Example 6 Treatment of Tissue Lesions Comprising administering a composition according to the invention:
In these examples, there was no objectification of the additive effect Combining RGTA and cell therapy because each case is isolated and unique which does not allow an objectification of the effects. The only criterion observed and likely to be studied is the improvement or not of the patient after treatment.
In this example, the effect of the composition according to the invention in the Pulmonary regeneration was studied. Patients with lesions of the pulmonary mucosa caused by exposure to vapors toxic fires inhaled RGTA 0TR4120 put in a spray and autologous adipocyte cells injected during the day even an hour after inhalation. The vaporizer contained a solution 30 to 100 microg.mL-1 of 0TR4120, and the inhalation was for 10 minutes allowing inhalation of about 5 mL. In the next half hour autologous cells taken the same day by liposuction (without concentration) were injected (5 mL IV). This administration was surprisingly and unexpectedly allowed a quick recovery and functional function of the patient, namely improved breathing while the treated patient was in therapeutic failure for several months.
In this example, the effect of the composition according to the invention on tissue injured following stent placement was observed. To do this, Oral administration of RGTA was made on the day of the place of the stent and followed after 24h the administration of autologous cells IV adipocytes (from a 50 mL liposuction) Oral RGTA 0TR4120 was 50 mL of a 100 microg.mL-1 solution was maintained for 1 month. The injection of cells repeated at 10 J and Days Recolonization of the injured area after stenting was Observed but undocumented showing surprisingly endothelization of the stent implantation area, which had never been observed with RGTA alone or cells alone.
In this example, the effect of the composition according to the invention on injured tissues here a muscle irradiated accidentally and having suffered a loss 20 functional its function. To do this an oral administration of RGTA
that is 25 mL to 100 mg / mL for two days followed by administration in the area of the irradiated muscle of cells, namely 5 injections of 1 mL
a solution of cells from 50 mL of marrow bone removed from the iliac fossa the same day and enriched by centrifugation and suspended in 5 mL of saline. Following the administration an evaluation of its functional activity was carried out.

Surprisingly and unexpectedly, the treatment allowed a functional motor recovery which seemed impossible.
In this example, the effect of the composition according to the invention on the re-epithelialization of the cornea has been studied. To do this a seeding on the day of collection of cells taken from mucous membranes of the patient on previously treated corneas locally by two drops of RGTA per cornea was performed. This treatment made it possible to obtain repair of the damaged tissue and in particular the effect has been greatly increased by the administration of CACICOL
alone.
Finally, an evaluation of the effect of an example of composition the invention on a spinal cord injury was also performed.
A 20-year-old patient had impaired motor function following a recent injury to the spinal cord rendering him paralyzed legs. A three-day treatment using an example of composition according to the invention for which the amounts of RGTA and cells were 25 mL / day of oral RGTA, respectively.
100 mg / mL solution of 0TR4120 and local injection (in the peripheral of the spinal cord injury) of 1 mL at 4 points cells from a 50 mL puncture of bone marrow from of the iliac fossa. This injection was renewed at 10 and 20 days then that the daily oral intake of RGTA was maintained during a duration of two months.
Unexpectedly and very positively, the patient started to recover a small neuro-motor function after the first three days of treatment days and gradually a significant improvement until a motor recovery.

Claims (27)

1. Pharmaceutical or dermatological composition for its application as a medicine for the prevention and / or treatment of tissue lesions, said composition comprising a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and a eukaryotic cell. 2. Pharmaceutical or dermatological composition for its application as a medicine for the prevention and / or treatment of tissue lesions, said composition comprising a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and - an extract and / or platelet lysate 3. Pharmaceutical or dermatological composition for its application as a medicine for the prevention and / or treatment of tissue lesions, said composition comprising a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and - At least one growth factor. 4. Composition for its application according to any one of Claims 1 to 3, wherein the monomers A are identical or different are selected from sugars, esters, alcohols, acids amino acids, nucleotides, nucleic acids, proteins or derived from them. 5. Composition for its application according to any one of Claims 1 to 4, wherein the monomers A are identical or different are selected from the sugars or derivatives thereof. 6. Composition for its application according to any one of Claims 1 to 5, wherein a maximum of 20% of the monomers A are independently monomers of the following formula:
wherein R9 and R10 independently represent an atom of oxygen, an aliphatic hydrocarbon chain, optionally branched and / or unsaturated, a heteroaryl group independently comprising one or several oxygen and / or nitrogen atoms, an aldehyde function, a carboxylic acid group, a diol, a substituted diol, a group of formula -R11- (X) n-R12 in which R11 represents a carbon chain C 1 -C 4 aliphatic, optionally branched and / or unsaturated, X
represents a heteroatom selected from oxygen and nitrogen, n is a integer from 1 to 4 and R12 is a hydrogen atom, a chain aliphatic hydrocarbon, optionally branched and / or unsaturated, a heteroaryl group independently comprising one or more atoms of oxygen and / or nitrogen, an aldehyde function, an acid group carboxylic acid, a diol, a substituted diol. 7. Composition for its application according to any one of Claims 1 to 6, wherein the number of monomers a is such that the mass of said polymers of formula (I) is greater than 2000 daltons. 8. Composition for its application according to any one of Claims 1 to 7, in which the substitution rate x is included between 20 and 150%. 9. Composition for its application according to any one of preceding claims, wherein the substitution rate is between 30 and 150%. 10. Composition for its application according to any one of preceding claims, characterized in that the radical R is chosen from an alkyl, allyl, aryl, linear or branched group. 11. Composition for its application according to any one of preceding claims, wherein said polymer biocompatible further comprises functional chemical groups Z, different from X and Y, capable of conferring on said polymer properties additional biological or physicochemical 12. Composition for its application according to claim 11, in which the substitution rate z of all the monomers A by Z groups are from 0 to 50%. 13. Composition for its application according to claim 11 or 12, in which the group Z is a substance capable of conferring said polymers have a better solubility or lipophilicity. 14. Composition for its application according to claim 13, in which which groups Z are identical or different and are chosen in the group comprising amino acids, fatty acids, fatty alcohols, ceramides, or derivatives thereof, or nucleotide sequences of addressing. 15. Composition for its application according to any one of Claims 6 to 14 in which the groups R9 and R10 are independently and optionally substituted with a Z group. 16. Composition for its application according to claim 1 or one of any of claims 4 to 15 when dependent on the claim 1 wherein the eukaryotic cell is selected from group comprising adult or embryonic eukaryotic cells, bone marrow cells, adipose tissue cells. 17. Composition for its application claim 1 or one any of claims 4 to 16 when dependent on the claim 1 wherein said biocompatible polymer is administered in the treatment of tissue lesions by:
- intravenously or intramuscularly at one dose 0.1 to 5 mg / kg body weight, or by local injection at a dose of 1 to 100 micrograms per milliliter, - Orally in 2 to 5 equal doses per day for a total of daily from 10 microg to 5 mg / kg body weight - Sublingual fasting of a concentrated aqueous solution of 1 at 100mg / mL, by aerosol administration or nasal spray of a solution, and wherein said eukaryotic cell is administered in the treatment injection tissue lesions within 5 minutes to 24h after the first intake of said biocompatible polymer. 18. Composition for its application according to claim 1 or one of any of claims 4 to 17 when they do not depend on the claim 2 or 3 wherein the composition comprises at least one growth factor selected from the group comprising the fibroblast growth (FGF), vascular growth factor endothelial (VEGF), platelet-derived growth factor (PGDF) or a mixture thereof. 19. Composition for its application according to claim 1 or one of any of claims 4 to 18 when not dependent on the claim 2 or 3 wherein the composition comprises an extract platelet and / or platelet lysate. 20. Composition for its application according to any one of preceding claims in which the tissue lesions are selected from the lesions of the locomotor system, vascular lesions, heart lesions, lesions of the central nervous system preferably to the exception of ischemic lesions of the central nervous system, lesions peripheral nervous system, lesions of sensory systems, lesions of the respiratory nervous system, lesions of the digestive tract, bone tissue lesions, pancreatic tissue lesions, lesions liver tissue, renal tissue lesions, pathway lesions urinary tract and / or vaginal tissue lesions, preferably with the exception of ischemic lesions of the lower limbs. 21. Pharmaceutical kit for use in prevention and / or tissue lesion treatment comprising:
i. a biocompatible polymer of general formula (I) below AaXxYy (1) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and ii. a eukaryotic cell. 22. Pharmaceutical kit for use according to claim 21 in which the biocompatible polymer is usable - intravenously or intramuscularly at one dose 0.1 to 5 mg / kg body weight, or - Orally in 2 to 5 equal doses per day for a total of daily from 1.5 to 500 mg, - intracranial at a dose of 0.001 to 1mg.mL-1 - Sublingual fasting of a concentrated aqueous solution from 1 to 100mg.mL-1, - by air by sprinkling a solution comprising 0.1 to 5 mg / kg of body weight of said polymer, and wherein said eukaryotic cell is usable for injection into a delay of 5 minutes to 24 hours after the first administration of said polymer biocompatible. 23.Pharmaceutical kit for use according to claim 21 or 22 in which the biocompatible polymer and / or said cell are administered over a period of one day to 3 months. 24.Pharmaceutical kit for use in any one of Claims 21 to 23, wherein the biocompatible polymer and / or said cell in which the administration is daily, twice daily or weekly. 25. Use of a pharmaceutical composition comprising i. a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and ii. a eukaryotic cell for the manufacture of a medicament for the treatment of lesions tissue. 26. Use of a pharmaceutical composition comprising i. a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and ii. an extract and / or platelet lysate for the manufacture of a medicament for the treatment of lesions tissue. 27. Use of a pharmaceutical composition comprising i. a biocompatible polymer of general formula (I) below AaXxYy (I) in which :
A represents a monomer, X represents a group R1COOR2, Y represents an O or N-sulphonate group and corresponding to one following formulas ¨R3OSO3R4, -R5NSO3R6 in which:
R1, R3 and R5 independently represent a chain aliphatic hydrocarbon, optionally branched and / or unsaturated and optionally which contains one or more aromatic rings and R2, R4 and R6 independently represent a hydrogen atom or a cation, a represents the number of monomers, x represents the degree of substitution of the monomers A by X groupings, y represents the degree of substitution of the monomers A by Y groupings, and ii. at least one growth factor for the manufacture of a medicament for the treatment of lesions tissue.